Patients with hepatitis C often remain asymptomatic for many years before problems appear, and when they do it may be too late, with fibrosis, cirrhosis and liver cancer all common, leading ultimately to liver failure.
If the virus is detected earlier, then the standard treatment is with the antiviral agent ribavirin plus interferon, but as few as half of patients respond to this therapy, and there is little in the way of alternatives. As a result, numerous novel antiviral agents are under development, including Merck & Co’s vaniprevir, an inhibitor of HCV NS3/4A protease.1
In a placebo-controlled Phase I trial 40 patients with chronic HCV genotype 1 infection were given daily or twice-daily doses of vaniprevir between 25 and 700mg for eight days as monotherapy.2 The highest reduction in viral load was seen in those patients given 700mg twice a day. There were no serious adverse events, and less severe side-effects included nausea, diarrhoea, constipation and headache.
A randomised, double-blind, placebo-controlled Phase II trial has also been carried out, with vaniprevir being administered in combination with interferon and ribavirin for 28 days to previously untreated patients with chronic HCV infection.3
Subjects were given 300 or 600mg twice a day, 600 or 800mg once a day, or placebo, and then continued with interferon and ribavirin therapy for a further 44 weeks. Four of the nine patients had viral breakthrough during dosing with vaniprevir, all of whom had a variant of the virus that is associated with reduced susceptibility to vaniprevir. Five experienced virological failure after the vaniprevir doses. Several further Phase II trials are under way.
1. J.A. McCauley et al. J. Med. Chem. 2010, 53, 2443
2. clinicaltrials.gov, NCT00518622
3. R.J.O. Barnard et al. Antivir. Ther. 2010, 15 (Suppl. 2), A24